DESCRIPTION: The applicants hypothesize that assessment of NK cell development and function in patients with HIV-1 infection will provide insights into how the human immune system can be better modulated to control HIV-1 replication and to improve the host response to infection. The specific aims of the proposal are: 1) to assess human NK cell differentiation from CD34+ hematopoietic bone marrow progenitor cells in patients with controlled and uncontrolled HIV-1 infection; 2) to assess the macrophage-NK innate immune effector arm in patients with controlled and uncontrolled HIV-1 infection following infectious insult in vitro; and 3) to assess NK cells obtained from patients with controlled and uncontrolled HIV-1 infection for their ability to suppress HIV-1 replication in vitro. To accomplish these objectives, the applicants propose to study 40 patients with HIV-1 infection stratified into 4 cohorts based on anti-retroviral medication, viral load and absolute CD4 cell count. They will also include 20 age-matched normal controls. Bone marrow stromal cells will be purified using methods previously developed in the applicant's laboratory and these cells will also be used to evaluate NK cell differentiation from purified CD34+ hematopoietic progenitor cells (HPC) in the presence of IL-15, KL and FL. In specific aim 2, a monocyte-NK cell co-culture system that has previously been developed will be used to assess the ability of monocytes to secrete monokines in response to various stimuli as well as the ability of NK cells to respond to endogenous monokine stimulation through the production of IFN-gamma. Specific aim 3 will examine the ability of supernatants from monokine-stimulated NK cells to suppress HIV-1 replication in vitro. These studies will examine both M-tropic and T-tropic strains of HIV.